US10196360B2 - Crystal forms of bedaquiline fumarate and preparation methods therefor - Google Patents

Crystal forms of bedaquiline fumarate and preparation methods therefor Download PDF

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US10196360B2
US10196360B2 US15/760,090 US201515760090A US10196360B2 US 10196360 B2 US10196360 B2 US 10196360B2 US 201515760090 A US201515760090 A US 201515760090A US 10196360 B2 US10196360 B2 US 10196360B2
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crystal form
bedaquiline fumarate
fumarate
bedaquiline
filtered
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US20180265473A1 (en
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Jinyi Xu
Liang Zhang
Xiangyang Zhang
Xinzeng Wang
Jian Chai
Hongying LUO
Zhiqing Yang
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Zhejiang Hisun Pharmaceutical Co Ltd
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Assigned to ZHEJIANG HISUN PHARMACEUTICAL CO., LTD. reassignment ZHEJIANG HISUN PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZHANG, XIANGYANG, YANG, Zhiqing, WANG, Xinzeng, CHAI, Jian, LUO, Hongying, XU, Jinyi, ZHANG, LIANG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0063—Control or regulation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of pharmacy. More specifically, the present invention relates to new crystal forms of bedaquiline fumarate and the preparation methods thereof.
  • Bedaquiline fumarate is a new type of anti-tuberculosis drugs, is a biaryl quinoline antibiotics, bactericide for the Mycobacterium tuberculosis , the main mechanism of action of bedaquiline fumarate is to inhibit the synthase of adenosine triphosphate (ATP) of Mycobacterium tuberculosis , block the energy supply of bacteria.
  • Bedaquiline has the same bactericidal activity against the common and drug resistant (including multidrug-resistant) strains of Mycobacterium tuberculosis , is not cross-resistant to existing antituberculosis drugs and is equally effective against dormant bacteria.
  • bedaquiline fumarate (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-1-phenyl-2-(1-naphthyl)-2-butan of fumarate, the structural formula is:
  • crystal forms may have different physicochemical properties including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, which directly affect the quality of the drug substance and the formulation.
  • the present invention relates to new crystal forms of bedaquiline fumarate, namely crystal form I, crystal form II and crystal form III.
  • One of the objects of the present invention is to provide crystal form I of bedaquiline fumarate.
  • the X-ray powder diffraction pattern of the crystal form I of bedaquiline fumarate provided by the present invention has characteristic peaks at 2 ⁇ (°) values of 5.6 ⁇ 0.2, 11.2 ⁇ 0.2, 22.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.6 ⁇ 0.2, 29.0 ⁇ 0.2.
  • X-ray powder diffraction pattern of the crystal form I of bedaquiline fumarate provided by the present invention also has characteristic peaks at 2 ⁇ (°) values of 3.8 ⁇ 0.2, 16.9 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 20.6 ⁇ 0.2, 20.9 ⁇ 0.2, 21.9 ⁇ 0.2, 26.7 ⁇ 0.2, 28.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the crystal form I of bedaquiline fumarate provided by the present invention has 2 ⁇ , d( ⁇ ) and relative intensity data as shown in the following Table 1:
  • the crystal form I of bedaquiline fumarate of the present invention has an X-ray powder diffraction pattern as shown in FIG. 1 .
  • the molecular stereoscopic projection of the crystal form I of bedaquiline fumarate of the present invention is shown in FIG. 2 .
  • the unit cell accumulation projection of the crystal form I of bedaquiline fumarate of the present invention along the b axis is shown in FIG. 3 .
  • the crystal form I of bedaquiline fumarate of the present invention can be characterized by the infrared absorption spectrum measured by KBr pellet, it has characteristic peaks at about 3408.88 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 2643.66 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1653.53 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1314.86 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1271.71 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 864.48 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 787.56 cm ⁇ 1 ⁇ 2 cm ⁇ 1 .
  • the infrared absorption spectrum of the crystal form I of bedaquiline fumarate has characteristic peaks at about 3408.02 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 3051.07 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 2945.75 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 2895.89 cm ⁇ 11 ⁇ 2 cm ⁇ 1 , 2643.66 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 2466.88 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1701.54 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1653.53 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1617.64 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1597.35 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1568.56 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1511.54 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1489.43 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1458.54 cm ⁇ 1
  • the infrared spectrum of the crystal form I of bedaquiline fumarate is shown in FIG. 4 .
  • the differential scanning calorimetry (DSC) thermogram of the crystal form I of bedaquiline fumarate of the present invention has a maximum absorption peak within the range of 205-210° C.
  • the DSC thermogram of the crystal form I of bedaquiline fumarate of the present invention is shown in FIG. 5 .
  • the TGA thermogram of the crystal form I of bedaquiline fumarate of the present invention is shown in FIG. 6 .
  • Another object of the present invention is to provide crystal form II of bedaquiline fumarate.
  • the X-ray powder diffraction pattern of the crystal form II of bedaquiline fumarate provided by the present invention has characteristic peaks at 2 ⁇ (°) values of 4.7 ⁇ 0.2, 7.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.5 ⁇ 0.2, 16.8 ⁇ 0.2, 18.7 ⁇ 0.2, 19.9 ⁇ 0.2, 21.5 ⁇ 0.2, 21.9 ⁇ 0.2, 24.3 ⁇ 0.2.
  • X-ray powder diffraction pattern of the crystal form II of bedaquiline fumarate provided by the present invention has characteristic peaks at 2 ⁇ (°) values of 3.4 ⁇ 0.2, 8.4 ⁇ 0.2, 11.6 ⁇ 0.2, 12.6 ⁇ 0.2, 14.9 ⁇ 0.2, 20.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the crystal form II of bedaquiline fumarate f the present invention has 2 ⁇ , d( ⁇ ) and relative intensity data as shown in the following Table 2:
  • the crystal form II of bedaquiline fumarate of the present invention has an X-ray powder diffraction pattern as shown in FIG. 7 .
  • the crystal form II of bedaquiline fumarate of the present invention can be characterized by the infrared absorption spectrum measured by KBr pellet, it has characteristic peaks at about 3408.88 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 2643.66 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1721.80 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1314.86 cm ⁇ 1 +2 cm ⁇ 1 , 865.79 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 776.91 cm ⁇ 1 ⁇ 2 cm ⁇ 1 .
  • the infrared spectrum of the crystal form II of bedaquiline fumarate is shown in FIG. 8 .
  • the differential scanning calorimetry (DSC) thermogram of the crystal form II of bedaquiline fumarate of the present invention has a maximum absorption peak within the range of 205-210° C.
  • the DSC thermogram of the crystal form II of bedaquiline fumarate of the present invention is shown in FIG. 9 .
  • the TGA thermogram of the crystal form II of bedaquiline fumarate of the present invention is shown in FIG. 10 .
  • Another object of the present invention is to provide crystal form III of bedaquiline fumarate.
  • the X-ray powder diffraction pattern of the crystal form III of bedaquiline fumarate provided by the present invention has characteristic peaks at 2 ⁇ (°) values of 6.1 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 14.1 ⁇ 0.2, 16.9 ⁇ 0.2, 18.9 ⁇ 0.2, 20.5 ⁇ 0.2, 20.8 ⁇ 0.2, 21.5 ⁇ 0.2, 23.2 ⁇ 0.2.
  • X-ray powder diffraction pattern of the crystal form III of bedaquiline fumarate provided by the present invention has characteristic peaks at 2 ⁇ (°) values of 13.2 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 24.9 ⁇ 0.2, 26.9 ⁇ 0.2, 27.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the crystal form III of bedaquiline fumarate of the present invention has 2 ⁇ , d( ⁇ ) and relative intensity data as shown in the following Table 3:
  • the crystal form III of bedaquiline fumarate of the present invention has an X-ray powder diffraction pattern as shown in FIG. 11 .
  • the crystal form III of bedaquiline fumarate of the present invention can be characterized by the infrared absorption spectrum measured by KBr pellet, it has characteristic peaks at about 1700.95 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1636.91 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1597.23 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1563.58 cm ⁇ 1 +2 cm ⁇ 1 , 1490.53 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1459.10 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1392.58 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1342.09 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1251.42 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1168.11 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1059.74 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 922.20 cm ⁇ 1 ⁇ 2 cm ⁇ 1 .
  • the infrared spectrum of the crystal form III of bedaquiline fumarate is shown in FIG. 12 .
  • the differential scanning calorimetry (DSC) thermogram of the crystal form III of bedaquiline fumarate of the present invention has a maximum absorption peak within the range of 205-207° C.
  • the DSC thermogram of the crystal form III of bedaquiline fumarate of the present invention is shown in FIG. 13 .
  • the TGA thermogram of the crystal form III of bedaquiline fumarate of the present invention is shown in FIG. 14 .
  • Another object of the present invention is to provide a method for preparing crystal form I of bedaquiline fumarate comprising the following steps:
  • the weight-to-volume ratio of bedaquiline fumarate to the mixed solvent of methanol and water is 1:10-50 g/ml, preferably 1:10-20 g/ml; the volume percentage of water is preferably 10%-70%, more preferably 20%-40%.
  • Another object of the present invention is to provide a method for preparing crystal form II of bedaquiline fumarate comprising the following steps:
  • (1)(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-1-phenyl-2-(1-naphthyl)-2-butanol fumarate is dissolved in a mixed solvent of methanol and ethyl acetate or a mixed solvent of methanol and ethanol;
  • the weight-to-volume ratio of bedaquiline fumarate to the mixed solvent of methanol and ethyl acetate is 1:1-20 g/ml, preferably 1:5-10 g/ml; the volume percentage of methanol in the mixed solvent is 40%-99%, preferably 50%-70%.
  • the weight-to-volume ratio of bedaquiline fumarate to the mixed solvent of methanol and ethanol is 1:1-20 g/ml, preferably 1:5-15 g/ml; the volume percentage of methanol in the mixed solvent is 40%-80%, preferably 50%-60%.
  • a further object of the present invention is to provide a method for preparing crystal form III of bedaquiline fumarate comprising the following steps:
  • the X-ray powder diffractometer (XRPD) and the test conditions involved in the present invention are: X-ray powder diffractometer model Rigaku D/max-2200 Cu target; operation method: scanning speed 4°/min, scanning step width 0.01°.
  • the infrared spectrophotometer and the test conditions involved in the present invention are: infrared spectrophotometer model: BRWKER VECTOR 22; operation method: using KBr pellet method, scanning range 400-4000 cm ⁇ 1 .
  • test conditions for DSC involved in the present invention are: differential scanning calorimeter model: NETZSCH DSC200 F3 Maia; operation method: heating rate 10° C./min, temperature range: 30° C.-250° C.
  • test conditions for TGA involved in the present invention are: thermogravimetric analyzer model: PerkinElmer TGA400; operation method: heating rate 10° C./min, temperature range: 30° C.-300° C.
  • the test conditions for the particle size involved in the present invention are: Mastersizer model: Mastersizer 2000; operation method: 20 mg of bedaquiline fumarate sample is taken, about 5.0 ml dispersant (n-hexane) is added, the sample is subjected to ultrasonication for 1.0 min, is allowed to stabilize for 0.5-1.0 min and then is tested.
  • test conditions for liquid chromatography involved in the present invention are: chromatographic column: Ultimate AQ C18, 250 ⁇ 4.6 mm, 5 ⁇ m; mobile phase A: acetonitrile and 0.1% trifluoroacetic acid, mobile phase B: water and 0.1% trifluoroacetic acid; detection wavelength: 220 nm; flow rate: 1 ml/min; injection volume: 10 ⁇ l.
  • the inventors of the present invention found that the new crystal forms of bedaquiline fumarate successfully improve the deficiencies of the prior art, and the drugs comprising the crystal forms of the present invention have the advantages of high purities and excellent physical and chemical properties, good stability, the crystallization methods thereof can effectively improve product quality and can be effectively used in the preparation of drugs and large-scale production and so on.
  • FIG. 1 is an X-ray powder diffraction pattern of crystal form I of bedaquiline fumarate obtained in Example 1.
  • FIG. 2 is molecular stereoscopic projection of crystal form I of bedaquiline fumarate obtained in Example 1.
  • FIG. 3 is the unit cell accumulation projection of crystal form I of bedaquiline fumarate obtained in Example 1 along the b axis.
  • FIG. 4 is an infrared absorption spectrum of crystal form I of bedaquiline fumarate obtained in Example 1.
  • FIG. 5 is a DSC thermogram of crystal form I of bedaquiline fumarate obtained in Example 1.
  • FIG. 6 is a TGA thermogram of crystal form I of bedaquiline fumarate obtained in Example 1.
  • FIG. 7 is an X-ray powder diffraction pattern of crystal form II of bedaquiline fumarate obtained in Example 6.
  • FIG. 8 is an infrared absorption spectrum of crystal form II of bedaquiline fumarate obtained in Example 6.
  • FIG. 9 is a DSC thermogram of crystal form II of bedaquiline fumarate obtained in Example 6.
  • FIG. 10 is a TGA thermogram of crystal form II of bedaquiline fumarate obtained in Example 6.
  • FIG. 11 is an X-ray powder diffraction pattern of crystal form III of bedaquiline fumarate obtained in Example 12.
  • FIG. 12 is an infrared absorption spectrum of crystal form III of bedaquiline fumarate obtained in Example 12.
  • FIG. 13 is a DSC thermogram of crystal form III of bedaquiline fumarate obtained in Example 12.
  • FIG. 14 is a TGA thermogram of crystal form III of bedaquiline fumarate obtained in Example 12.
  • the crystal form I, crystal form II and crystal form III of bedaquiline fumarate prepared respectively in Example 1, Example 6 and Example 12 of the present invention were selected for test of particle size.
  • Test Procedure the Hydro2000SM injector was connected and the Small Volume Sample Dispersion Unit tachometer was turned on, then a suitable amount of ethanol was added to the sample cell to clean the detection channel of the instrument.
  • a suitable amount of n-hexane (dispersant) was added to the dispersion cup, a suitable amount of n-hexane (dispersant) was inlet into the instrument to exhaust gas, the stirring rate was set to 2950 rpm, optical correction and background measurement were carried out.
  • the suspension was added to the sample cell until the opacity was between 15% to 20%, the suspension was allowed to stabilize for 0.5-1.0 min, the measurement time was 4 sec, the test results was saved automatically by the system.
  • the test results show that the particle sizes of the crystal form I and crystal form II of bedaquiline fumarate were smaller than that of the crystal form III.
  • the smaller the particle size, the bigger the specific surface area, and bigger specific surface area was conducive to improving the dissolution behavior, and the improved dissolution behavior was considered to improve the bioavailability.
  • the particles of the three crystal forms were dispersed homogeneously, in the actual production, a step of micronization or screening process was reduced and costs were saved.
  • Table 6 shows the solubility data of the different crystal forms prepared in the present invention in different solvents at 50° C.
  • the crystal form I, the crystal form II and the crystal form III of bedaquiline fumarate prepared respectively in Example 1, Example 6 and Example 12 of the present invention were selected for solubility test.
  • Table 7 shows the test results of stability by liquid chromatography of the different crystal forms prepared according to the present invention at a temperature of 60° C. and a humidity of 75% for 6 months.
  • Example 1 The crystal form I, the crystal form II and the crystal form III of bedaquiline fumarate prepared respectively in Example 1, Example 6 and Example 12 of the present invention were selected for liquid chromatography test.

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  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Quinoline Compounds (AREA)
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RS65207B1 (sr) * 2017-07-14 2024-03-29 Janssen Pharmaceutica Nv Formulacije bedakvilina sa dugim delovanjem
KR102303635B1 (ko) * 2020-07-01 2021-09-17 동아에스티 주식회사 (1r,2s)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 이의 약제학적으로 허용 가능한 염의 제조방법
CN111606850B (zh) * 2020-07-07 2023-07-25 安徽贝克生物制药有限公司 贝达喹啉及其中间体的制备方法

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US20050148581A1 (en) 2002-07-25 2005-07-07 Van Gestel Jozef F.E. Novel mycobacterial inhibitors
CN1976704A (zh) 2004-05-28 2007-06-06 詹森药业有限公司 取代的喹啉衍生物在治疗耐药性分枝杆菌性疾病中的用途
WO2008068231A1 (fr) 2006-12-05 2008-06-12 Janssen Pharmaceutica N.V. Sel de fumarate de (alpha s, bêta r)-6-bromo-alpha-[2-(diméthylamino)éthyl]-2-méthoxy-alpha-1-naphtalényl-bêta-phényl-3-quinoléineéthanol
WO2016058564A1 (fr) * 2014-10-16 2016-04-21 Zentiva, K.S. Sels de bédaquiline

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CN106316943A (zh) * 2016-07-27 2017-01-11 重庆华邦制药有限公司 富马酸贝达喹啉晶型化合物的精制方法

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CN1671667A (zh) 2002-07-25 2005-09-21 詹森药业有限公司 喹啉衍生物及其作为分枝杆菌抑制剂的应用
CN1976704A (zh) 2004-05-28 2007-06-06 詹森药业有限公司 取代的喹啉衍生物在治疗耐药性分枝杆菌性疾病中的用途
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WO2008068231A1 (fr) 2006-12-05 2008-06-12 Janssen Pharmaceutica N.V. Sel de fumarate de (alpha s, bêta r)-6-bromo-alpha-[2-(diméthylamino)éthyl]-2-méthoxy-alpha-1-naphtalényl-bêta-phényl-3-quinoléineéthanol
CN101547904A (zh) 2006-12-05 2009-09-30 詹森药业有限公司 (αS，βR)-6-溴-α-[2-(二甲胺基)乙基]-2-甲氧基-α-1-萘基-β-苯基-3-喹啉乙醇的富马酸盐
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CN108349898B (zh) 2021-03-23
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RU2018111482A3 (fr) 2019-11-21
EP3366676A4 (fr) 2019-06-12
US20180265473A1 (en) 2018-09-20
WO2017066926A1 (fr) 2017-04-27
KR102106318B1 (ko) 2020-05-06
CN108349898A (zh) 2018-07-31
KR20180059941A (ko) 2018-06-05
EP3366676A1 (fr) 2018-08-29

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